Abstract 10172: Q Neurons-Induced Hypometabolism Ameliorates Acute Kidney Injury Associated With Renal Ischemia in a Mouse Model Mimicking Cardiovascular Surgery Requiring Circulatory Arrest

Abstract

Introduction: Acute kidney injury (AKI) is a serious complication after cardiovascular surgery requiring circulatory arrest and hypothermia has been used for organ protection. We recently reported that mice can be induced into a hibernation-like hypometabolic state by the stimulation of a specific neuron producing pyroglutamylated RFamide peptide (QRFP) located at hypothalamus (Q neurons-induced hypometabolism; QIH). Here, we investigated the efficacy of QIH for the amelioration of AKI in an experimental circulatory arrest under normal and reduced body temperature using a transgenic mouse model in which QIH can be induced. Methods: We genetically prepared mice in which Q neurons specifically express iCre, a Cre recombinase (Qrfp iCre mice), from male C57/B6J mice. To prepare QIH-ready mice, we intracranially injected AAV8-hSyn-DIO-hM3-mCherry targeting hypothalamus for specific expression of hM3Dq in which QIH can be induced by intraperitoneal injection (i.p.) of clozapine-N-oxide (CNO), an agonist of hM3Dq. For the control, we injected AAV8-hSyn-DIO-mCherry. Mice were divided into 4 groups (n=6 for each): QIH-ready; normothermia (QN), QIH-ready; hypothermia (QH), control; normothermia (CN), and control; hypothermia (CH). At 3 hours after CNO i.p., left thoracotomy and 15-minutes descending aorta cross-clamping were conducted. After re-perfusion, we collected kidneys and evaluated histological changes and serum biochemical markers, neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin C indicating early kidney injury. Results: Normothermia showed higher tubular injury scores than those in hypothermia (QN vs QH: p=0.0021, CN vs CH: p<0.001). QN showed a lower tendency than CN (CN vs QN: 3.0±1.1 vs 2.5±0.55, p=0.51). QN exhibited lower NGAL and Cystatin C levels than those in CN (NGAL: CN vs QN:1.51±0.71 vs 0.82±0.32, p=0.0414 / Cystatin C: 1.48±0.39 vs 0.71±0.26, p=0.0015). There was no significant difference between QN and QH (NGAL: 0.82±0.32 vs 0.44±0.13, p=0.411 / Cystatin C: 0.71±0.26 vs 0.65±0.22, p=0.987). Conclusions: QIH partly ameliorated AKI in a mouse ischemia model even in normothermia. QIH might be a promising approach to achieving sufficient kidney protection without hypothermic circulatory arrest in the future.